1. Field of the Invention
The present invention relates to a process for preparing pharmaceutically useful .alpha.-arylalkanoic acids. In particular, it relates to a stereoselective process for producing optically active .alpha.-arylalkanoic acids which are substantially optically pure.
2. State of the Art
Numerous .alpha.-arylalkanoic acids (i.e. 2-arylalkanoic acids) have been described, developed and found to be useful as pharmaceutical agents exhibiting anti-inflammatory, analgesic and anti-pyretic activity. For example, U.S. Pat. No. 3,385,386, describes certain 2-phenylpropionic acids useful for their anti-inflammatory activity. Particularly noteworthy of the compounds described therein is 2-(4-isobutylphenyl)propionic acid, known generically as ibuprofen. U.S. Pat. No. 3,600,437 describes 2-(3-phenoxyphenyl)-and 2-(3-phenylthiophenyl)alkanoic acids among other related compounds. Particularly noteworthy therein is the compound 2-(3-phenoxyphenyl)propionic acid, which is known generically as fenoprofen. U.S. Pat. No. 3,624,142 describes (fluoro-substituted biphenyl)alkanoic acids, among which is 2-(4'-fluoro-4-biphenylyl)propionic acid. U.S. Pat. No. 3,755,427 describes additional fluoro-substituted biphenylpropionic acids, among which is 2-(2-fluoro-4-biphenylyl)propionic acid, known as flurbiprofen. U.S. Pat. No. 3,904,682 describes the compound 2-(6-methoxy-2-naphthyl)propionic acid, the d-isomer of which is known generically as naproxen and is a potent anti-inflammatory compound. Related compounds are described in Belgian Pat. No. 747,812. U.S. Pat. No. 3,912,748 describes 5- and 6-benzoxyazoylalkanoic acids possessing anti-inflammatory, anti-pyrretic and analgesic activity. Notable among those compounds is 2-(4-chlorophenyl-5-benzoxazoyl)propionic acid, known generically as benoxaprofen. Thus, it can be seen that a tremendous variety of useful .alpha.-arylalkanoic acids are known.
Other known, useful .alpha.-arylalkanoic acids are exemplified by 6-chloro-.alpha.-methyl-9H-carbazole-2-acetic acid (carprofen), .alpha.-methyl-9H-fluorene-2-acetic acid (cicloprofen), 3-chloro-.alpha.-methyl-4-(2-thienylcarbonyl)benzene acetic acid (cliprofen), .alpha.-methyl-3-phenyl-7-benzofuranacetic acid (furaprofen), 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)benzene acetic acid (indoprofen), 3-benzoyl-.alpha.-methylbenzene acetic acid (ketoprofen), 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)benzeneacetic acid (pirprofen), .alpha.-methyl-4-(2-thienylcarbonyl)benzeneacetic acid (suprofen) and compounds related thereto. Additionally, certain pyrethroid-type insecticides utilize optically active .alpha.-arylalkanoic acids, e.g. .alpha.-(4-chlorophenyl)isovaleric acid, .alpha.-(4-difluoromethoxyphenyl)isovaleric acid and the like, in their formulations.
Numerous processes for the manufacture of such .alpha.-arylalkanoic acids have also been described. Such processes have been described in the aforementioned patents, in other patents and in the non-patent literature as well. For example, U.S. Pat. No. 4,135,051 describes a process for preparing the ester precursors of many of the useful arylalkanoic acids utilizing trivalent thallium salts as reactants. Such a process suffers from the disadvantage that the thallium salts employed are toxic chemicals which must be removed from the final product. U.S. Pat. No. 3,975,431 describes the preparation of .alpha.-arylalkanoic acids from glycidonitriles through enol acylates. U.S. Pat. Nos. 3,658,863; 3,663,584; 3,658,858; 3,694,476; and 3,959,364 describe various coupling methods for preparing arylalkanoic acids. More recently, U.K. Patent publication No. 2,042,543 published Sept. 24, 1980, (corresponding to application Ser. No. 8005752, filed Feb. 20, 1980) describes a process for preparing the ester precursor of arylalkanoic acids from .alpha.-haloalkyl aryl ketones using a metal catalyst for catalytically inducing rearrangement in an acidic, alcoholic medium, the catalyst being silver (I) salts of organic and/or inorganic anions. The high costs associated with utilizing metal catalysts, particularly silver, in a large scale process is an inherent disadvantage to such a process. European patent application Ser. No. 81200210.3, filed Feb. 23, 1981 (Publication No. 0034871, published Sept. 2, 1981) describes a process for preparing esters of .alpha.-arylalkanoic acids via rearrangement of .alpha.-haloketals in the presence of a Lewis acid (including, for example, copper and zinc salts and the like). Additionally, a recent article in Tetrahedron Letters, Vol. 22, No. 43, pp 4305-4308 (1981) describes a process for producing .alpha.-arylalkanoic acids by 1,2-rearrangement of the aryl group via hydrolysis of .alpha.-sulfonyloxy acetals.
While the aforesaid processes are useful in many respects, there remains a need for a simple, economical process for producing .alpha.-arylalkanoic acids of the types described. Furthermore, in view of the optically active nature of numerous of the .alpha.-arylalkanoic acids, it is advantageous to have a stereoselective process for producing the desired optically active isomer of the .alpha.-arylalkanoic acids which displays all or the major portion of the pharmaceutical activity. For example, the isomer d 2-(6-methoxy-2-naphthyl)propionic acid is more pharmaceutically active than the corresponding 1-isomer, and, accordingly, it is desireable to have a stereoselective process for producing the d-isomer directly. Such a process obviates the necessity of subsequently resolving the d- and 1-isomers. The elimination of the resolution steps results in substantial economic savings, both in material cost and manufacturing labor and plant usage. These savings are particularly significant with regard to those compounds which are approved for pharmaceutical use as a substantially pure, optically active isomer [e.g. d 2-(6-methoxy-2-naphthyl)propionic acid].